Diabetes is a major health concern in the United States, with 8.3% of the population affected. One promising treatment for diabetes is transplantation of insulin-producing pancreatic islets; however, there are issues with immune rejection making this procedure impractical for most patients. Testicular Sertoli cells (SC) are immune privileged cells that have been shown to survive and protect co-grafted islets when transplanted across immunological barriers in male and female diabetic rodents without immunosuppression. In fact, the male and female recipients maintained normal blood glucose levels long-term and were reproductively normal. However, the mechanism for this protection remains unresolved and more recent studies have shown that the protective ability is variable. Thus, if we are to improve the protection of co-transplanted SC/islet grafts as a treatment for diabetes, more information is needed on the mechanism of SC immune protection. Recently, we have observed a correlation between regulatory T cells and SC graft survival. In this proposal, we will test the hypothesis that immune privileged SC protect co-transplanted islets by inducing regulatory T cells and that the observed variability in islet graft survival is due to differences n the ability of SC to induce these regulatory T cells. In aim 1, the importance of regulatory T cell in SC protection of co-transplanted allogeneic islets will be determined by depleting the regulatory T cells and examining the effect on islet graft survival. In addition, whether mice injected with regulatory T cells isolated from successful SC/islet co-grafts prior to transplantatin with islets will improve the protection (decrease the variability) provided by SC will be tested. I aim 2, the mechanism for induction of regulatory T cells by SC will be examined by determining the importance of immunoregulatory factors expressed by SC in the induction of regulatory T cells. Collectively, these aims will determine the importance of regulatory T cells in SC protection of co-transplanted allogeneic islets. Further, they will provide information on how SC induces regulatory T cells and protect islet grafts. Ultimately understanding the mechanism for SC immune protection of islets is important because it has the potential to improve islet transplantation by eliminating the need for chronic immunosuppression.